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The Roles of Fibroblast Growth Factor 22 in Development, Tissue Repair and Homeostasis, and the Associated Role of FGF Signalling in Skin Cancer

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The Roles of Fibroblast Growth Factor 22 in Development, Tissue Repair and Homeostasis, and the Associated Role of FGF Signalling in Skin Cancer The roles of Fibroblast Growth Factor 22 in development, tissue repair and homeostasis, and the associated role of FGF signalling in skin cancer. Monika Jarosz This thesis is submitted in fulfilment of the requirements for the degree of Doctor of Philosophy University of London February 2010 Centre for Tumour Biology, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK DECLARATION OF AUTHORSHIP I hereby declare that the material presented in this thesis is the result of original work done by the author, Monika Jarosz, at the Department of Tumour Biology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London. All external sources have been properly acknowledged. 2 Abstract Fibroblast Growth Factors (FGFs) play critical roles during development, tissue homeostasis and repair and in controlling cell proliferation, survival, migration and differentiation. Of the 22 mammalian FGFs, FGF22, a member of the FGF7/10/22 subfamily, is relatively understudied. I have investigated the in vivo functions of FGF22 in mice engineered to lack Fgf22. Fgf22 null animals were viable, fertile and did not display any obvious abnormalities. No differences in skin histology and pelage hair were observed, demonstrating that FGF22 is dispensable during embryogenesis and in unchallenged adult skin. Mice lacking FGF22 were able to heal acute wounds just as efficiently as wild type mice. However, classical two-step skin carcinogenesis challenge revealed that Fgf22 null mice developed considerably less papillomas than wild type mice. Interestingly, Fgf22 knockout mice displayed a significant reduction in body weight and I identified several novel sites of Fgf22 expression in the gastrointestinal tract. However, the morphology and function of various tested tissues of the digestive system were not affected by Fgf22 deletion and the mechanism underlying metabolic differences between Fgf22 wild type and knockout mice remains unknown. FGF22 signals through FGFR2b, a receptor tyrosine kinase that we recently have shown plays a tumour-suppressive role in the mouse skin. Another aspect of my project was to verify whether FGFR2 plays a similar role in human skin, by investigating squamous cell carcinoma (SCC) sections and cell lines isolated from patient SCCs. I observed differences in the pattern of anti-FGFR2 3 immunostaining of normal skin and tumours. Also, since it is well documented that mutations in FGFR2 arise in patients with different types of cancer, I screened DNA isolated from the cell lines and identified eleven different mutations in FGFR2. This study contributes towards a better understanding of the wide spectrum of FGF/FGFR activities and distinct regulatory functions in the biology of physiological and pathological processes. 4 All truths are easy to understand once they are discovered; the point is to discover them. Galileo Galilei Science never solves a problem without creating ten more. George Bernard Shaw 5 Acknowledgements I would like to gratefully acknowledge the enthusiastic supervision of Dr Richard Grose during this work. I am deeply thankful for his wise guidance, great support and encouragement. I want to express heart-felt gratitude to my dearest friends Magdalena Nowak- Musial, Sabari Vallath and Marcus Pearce for being there for me. I am additionally indebted to Magda for her work and expertise on the retinal aspect of my project. I would also like to thank Prof Ian Hart and all my colleagues from the lab, especially Maria, Bernardo, Silvia, Fieke, Mike, Antonio, Sally, Monica, Carine, Louise, Katie and Ireny. It has been a great pleasure and fun working with you. Several people have played a decisive role in saving me from leaving FGFs forever. Richard, Sabari, Mum and Dad - without your support, care and consideration this PhD thesis would not have been written. I am very thankful to you all. I would also like to thank Barbara, Rob and Jenny for all their hard work in the animal unit at Clare Hall Laboratories, CRUK. Lastly, I would like to thank St Bartholomew's and the Royal London Charitable Foundation for the funding provided which allowed me to complete this work and fulfil my dreams. Dedication I would like to dedicate this thesis to my family, my mother Alicja, my father Jozef and my sister Kasia to whom I owe my deepest gratitude for their endless love and constant encouragement in pursuing my goals. 6 TABLE OF CONTENTS Title page 1 Declaration 2 Abstract 3 Acknowledgements 6 Dedication 6 Table of contents 7 List of figures 13 List of tables 16 Chapter 1: Introduction 17 1.1.1 The fibroblast growth factor family 18 1.1.2 FGF7 subfamily 20 1.2 Fibroblast growth factor receptors – structure and specificity 21 1.3 FGF signalling 24 1.4 FGF mutations in human birth defects 27 1.5 Fgf knockout mice phenotypes 30 7 1.6 FGFs in skin development and homeostasis 34 1.6.1 Skin structure 34 1.6.2 FGFs and wound healing 38 1.6.3 FGFs and skin carcinogenesis 44 1.7 FGFs and their receptors in cancer 46 1.8 Therapeutic approaches 48 Aims 50 Hypothesis 50 Chapter 2: Materials and methods 51 2.1 Materials 52 2.1.1 Chemicals and other consumables 52 2.1.2 Antibodies 57 2.1.3 Primers 59 2.1.3.1 Primers for genotyping 59 2.1.3.2 Primers for RT-PCR 60 2.1.3.3 Primers for Real-Time RT-PCR 60 2.1.3.4 Primers for sequencing 62 2.1.3.5 Mycoplasma screening primers 62 2.1.3.6 Loading control primers 62 2.2 Mice 63 2.2.1 Conditional knockout mice (K5-R2b null) 63 2.2.2 Creation of Fgf22 knockout mice 64 2.3 Genotyping, PCR and DNA gel electrophoresis 65 2.3.1 DNA isolation 65 8 2.3.2 Polymerase chain reaction (PCR) 66 2.3.3 Electrophoresis 67 2.4 RNA isolation 68 2.5 cDNA synthesis 69 2.6 PCR product digestion 71 2.7 Real-time Polymerase Chain Reaction (PCR) 73 2.8 TOPO cloning 75 2.8.1 TOPO TA cloning reaction 76 2.8.2 Transforming One Shot TOP10 competent cells 76 2.8.3 Plating bacteria 77 2.8.4 DNA Miniprep 77 2.8.5 PCR identification of positive clones 78 2.8.6 Plasmid extraction 78 2.9 Sequencing 79 2.9.1 Routine sequencing 79 2.9.2 Mutation screening sequencing 80 2.9.2.1 Labelling 80 2.9.2.2 Precipitation of labelled products 81 2.10 Cell lysis and Western blotting 81 2.10.1 Cell Lysis 81 2.10.2 Determination of protein concentration 82 2.10.3 Gel electrophoresis 82 2.10.4 Western blotting 83 2.10.5 FGFR2 Western blot 83 2.11 Genomic DNA extraction from cell monolayers 84 2.12 Southern Blotting 85 2.12.1 ES cell screening probe preparation 87 9 2.12.2 Probe labelling 88 2.12.3 Hybridisation 88 2.13 Tissue fixation and wax embedding 89 2.13.1 Eye dissection 89 2.13.2 Oesophagus and stomach dissection 90 2.14 Tail epidermis whole-mounts 91 2.15 Immunohistochemistry 92 2.15.1 -FGFR-2 antibody 92 2.15.2 -BrdU antibody 93 2.15.3 -p63 antibody 94 2.15.4 -Loricrin antibody 95 2.15.5 -Keratin14 antibody 96 2.16 Alcian Blue and Alizarin Red skeletal staining 96 2.17 Sirius red staining 97 2.18 ELISA 98 2.18.1 Sample collection and storage 95 2.18.2 Assay procedure 99 2.19 Basic cell culture 100 2.19.1 General principles 101 2.19.2 Tissue culture media and solutions 101 2.19.2.1 CR-UK stock media 101 2.19.2.2 Human SCC keratinocyte medium 101 2.19.2.3 Early passage HaCaT keratinocyte medium 102 2.19.2.4 Primary murine keratinocyte media 102 2.19.2.4.1 Preparation of calcium free FBS 102 2.19.3 Mycoplasma screening 102 2.19.4 Early passage HaCaT keratinocyte cell culture 104 10 2.19.5 Primary murine keratinocyte cell culture 104 2.19.5.1 Coating flasks for keratinocyte cell culture 106 2.19.5.2 Passaging primary keratinocytes 106 2.19.6 Storage and recovery of liquid nitrogen stocks 107 2.19.6.1 Cryopreservation of cultured cells 107 2.19.6.2 Thawing cell stocks 107 2.20 In vitro wound closure assay - Scratch assay 108 2.21 Organotypic co-culture 108 2.22 Mouse growth curves 110 2.23 In vivo wound healing 110 2.24 Topical administration of DMBA/PMA to mice 111 2.25 Micro CT 113 2.26 Ethical regulations 113 Chapter 3: Fibroblast growth factor 22 115 3.1 Introduction 115 3.1.1 Fgf22 expression profile 115 3.1.2 FGF signalling in hair follicle morphogenesis 116 3.1.3 FGFs in wound healing 119 3.1.4 FGFs in the brain 121 3.1.5 Other sites of Fgf22 expression 123 3.1.6 Properties of FGF22 protein 124 3.2 Results 127 3.2.1 Generation of Fgf22 knockout mice 127 3.2.2 Characterisation of Fgf22 knockout mice 134 3.3 Discussion 171 11 3.4 Future directions 180 Chapter 4: Fibroblast growth factor receptor 2 182 4.1 Introduction 183 4.1.1 The role of FGFRs in carcinogenesis 183 4.1.2 FGFR2 as a tumour suppressor 183 4.1.3 FGFR2 as an oncogene 187 4.1.4 FGFR2 germline mutations 191 4.1.5 Potential therapeutic approaches 193 4.2 Results 195 4.2.1 FGFR2 genomic sequence in SCC keratinocyte cell lines 195 4.2.2 FGFR2 mutation screening 198 4.2.3 SCC cell lines express the FGFR2IIIb splice isoform 204 4.2.4 FGFR2 expression in normal human skin and human 211 squamous cell carcinoma 4.3 Discussion 214 4.4 Future directions 219 Chapter 5: Final discussion 222 Appendix 232 Bibliography 248 12 LIST OF FIGURES Chapter 1: Introduction Figure 1.1 Fibroblast growth factor family.
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